Circulating serum preptin levels in women with polycystic ovary syndrome: A systematic review and meta-analysis

Abstract Background Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder with complex pathogenesis and metabolic complications, such as insulin resistance. Among the new markers, preptin seems to play a significant role in metabolic disorders. Objective This meta-analysis was conducted to determine the relationship between circulating preptin levels and PCOS. Materials and Methods A systematic review and meta-analysis was performed to identify relevant articles in electronic databases such as PubMed, Web of Science, Scopus, Cochrane, EMBASE, and the Google Scholar search engine, using a predefined search strategy. A random-effects model was used to combine standard mean difference (SMD) and 95% CI to compare results between groups. Meta-regression and subgroup analysis were also performed to reveal the sources of heterogeneity. Results The meta-analysis encompassed a total of 8 studies and 582 participants. The results indicate a statistically significant association between PCOS and serum preptin levels, with a pooled standardized mean difference (SMD = 1.35; 95% CI]: 0.63-2.08; p < 0.001). Further analysis suggested a significant difference in serum preptin levels between women with PCOS and higher homeostatic model assessment for insulin resistance ratio (SMD = 2.40; 95% CI: 1.17-3.63; p < 0.001) within the subgroup. Conclusion Our meta-analysis shows that increased serum preptin levels are associated with PCOS, suggesting that preptin may be related to the pathogenesis of PCOS and may be recognized as a novel diagnostic biomarker for PCOS. However, further studies are needed to confirm our results.


Introduction
Polycystic ovary syndrome (PCOS) is a prevalent endocrine and metabolic disease in women of gestational age (1). It is characterized by ovulation disorder, hyperandrogenism, and polycystic ovarian morphology (2). Women with PCOS may suffer from various problems, such as infertility, endocrine, and metabolic disorders (3).
The risk of depression and its symptoms appears to be higher in women with PCOS, which may be related to factors such as hyperinsulinemia, hyperandrogenism, and increased levels of inflammation (4,5).
The underlying cause of PCOS is unknown and probably multifactorial, which has implications for proposed treatments. Many studies have suggested that PCOS is caused due to ovarian abnormalities (6)(7)(8)(9). One criterion for PCOS is based on the Rotterdam criteria, which demands the presence of 3 features: hyperandrogenism, polycystic ovaries on ultrasound, and menstrual irregularities (10,11). In addition, PCOS is closely associated with obesity, insulin resistance (IR), impaired glucose tolerance, hypertension, type 2 diabetes mellitus, dyslipidemia, and cardiovascular disease (12). Recent studies on metabolism-regulating proteins and peptides have gained interest as potential biomarkers for PCOS disorders (13)(14)(15)(16).
Among the new markers involved in metabolic disorders, preptin is of great importance (17).
Preptin is a 34-amino acids hormone produced by the gene encoding insulin-like growth factor 2. This peptide is co-secreted with insulin in response to glucose from the pancreatic betacells and stimulates insulin secretion (18,19). The primary function of preptin involves the regulation of carbohydrate, protein, and lipid metabolism by modulating insulin secretion (20).
Studies show a direct relationship between preptin serum levels and the fasting homeostasis model assessment of insulin resistance (HOMA-IR) (21). Some studies have also showed the association between preptin serum levels and a high HOMA-IR in PCOS participants (18,22). However, the effect of preptin on the pathogenesis of PCOS is still unclear, and the results seem controversial (23,24) . Therefore, this meta-analysis aimed to analyze previous studies on the association between serum preptin levels and PCOS and to investigate whether preptin can be recommended as a new biomarker for PCOS.

Protocol and registration
This systematic review and meta-analysis were conducted according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines to ensure transparency and rigor in the review process (25,26). Our systematic review was registered in PROSPERO (the international database for prospectively registered systematic reviews).

Eligibility criteria
All the observational studies published from January 2000 to August 2022 that defined PCOS according to the Rotterdam criteria and reported serum/plasma or follicular fluid preptin levels in PCOS participants compared with non-PCOS controls were included (10). In addition, some studies were excluded for the following reasons: I) incorrect comparison subjects and study design such as interventional studies, II) review articles, studies not conducted in humans, and conference articles, III) studies with non-extractable data. to August 2022. The following keywords were used: "Preptin", "ProIGF-II", "Insulin-Like Growth Factor II", "polycystic ovary syndrome", "PCOS", "polycystic ovary" using coordinating conjunctions "AND" and "OR". Also, references to related articles were searched manually.

Literature search
Search terms were supplemented by searching for available gray literature. In addition, all records were entered into the EndNote 9 software, and duplicate studies were removed after the screening.

Study selection
2 independent reviewers thoroughly scanned the available literature to assess the eligibility criteria for the study (S.B. and M.D.). Any disagreements between the reviewers were resolved through collaborative discussion. In addition, a third reviewer was brought in to provide further insights and help reach a consensus (R.E.).

Data extraction
The following data were extracted according to a pre-prepared checklist: origin of study characteristics (name of first author, year of publication, and location of study), study design (cross-sectional, cohort, or case-  (Table I).  Each study was assigned a point scale of 9 stars, with ratings of 5-9 stars representing high quality, and ratings of 0-4 stars representing low quality.
Any discrepancies in the NOS rating of the studies were resolved through discussions among the authors. The quality assessment outcomes for all the included studies are presented in (Table II).

Characteristics of the included studies
The

Meta-regression analysis
The meta-regression for SMD of preptin level   Figure 7).

Publication bias and sensitivity analysis
However, it is essential to note that the Cochrane handbook for systematic reviews of interventions states that publication bias may be unreliable if fewer than 10 studies were conducted (40). We also performed a sensitivity analysis to confirm the stability and reliability of our outcome. The overall effect size did not change significantly when the individual studies were removed, indicating the reliability of the analysis.

Discussion
PCOS is a current endocrinal disorder.
This syndrome results in infertility, IR, obesity, cardiovascular problems, and other health problems (41). Preptin is an oligopeptide secreted by pancreatic β-cells that has emerged as a potential new biomarker for diagnosing of PCOS because of its role in promoting insulin secretion (42,43). These include the reality that the number of studies is insufficient due to the novelty of the topic. However, further studies with a larger statistical population could support our findings. In addition, the data collected for this research were based on English-language articles, and it was not possible to access non-English-language articles, abstracts, and dissertations. Finally, it should be noted that the results of this study require additional research and should be evaluated with caution.

Conclusion
Our meta-analysis revealed an association between serum preptin levels and PCOS participants, suggesting that preptin could be used as a novel biomarker for PCOS. Moreover, this association was influenced by IR.